Cell movements, signaling and establishment of epigenetic states in early mammalian development


Mammalian development can be viewed as a series of restrictions in cell potency. As the embryo undergoes cleavage, implantation and gastrulation, cell potency is gradually restricted (with the exception of the germline) until cells commit to a particular pathway of differentiation. This process depends on the generation of heritable epigenetic states that must be perpetuated as the embryo progresses in development. How are these epigenetic states established and maintained? In this issue of the Journal of Cellular Physiology, four articles summarize recent advances in our understanding of signaling events, cell movements and epigenetic mechanisms that control cell fate and shape the early mouse embryo.

X-inactivation is a prime example of an epigenetic phenomenon that regulates early mammalian development. Twenty years ago, the realization that Xist was responsible for silencing the X-chromosome (Brown et al., 1991), opened the door to fascinating epigenetic discoveries. Today, X-inactivation research continues to generate captivating and provocative results. As highlighted in the article by S. Kalantry, recent studies, suggest that there can be X-chromosome inactivation in the absence of Xist. In addition, RNF12 has been proposed to be at the core of the long sought counting mechanism by which a cell senses the number of X-chromosomes that it harbors.

The article by Trask and Mager examines the role of chromatin remodeling complexes in the establishment and maintenance of embryonic epigenetic marks. Interestingly, this field of research was greatly aided by the positional cloning of Eed (Schumacher et al., 1996), a lethal mutation that affects gastrulation and whose gene codes for a member of the polycomb repressive complex 2 (PRC2). Eed mutants have been instrumental in studies that linked PRC2 to the maintenance of chromatin modifications leading to imprinted and random X-inactivation. Since then a plethora of members of the PRC2 and other chromatin remodeling complexes have been identified in mice and the search continues for the identification of polycomb responsive elements in the genome.

Sunmonu and co-workers explore the role of Fgf8, a gene required for cell movements during gastrulation that, like Eed, is essential for embryo survival (Sun et al., 1999). Fgf8 has multiple pleiotropic effects and is required later for brain, limb and craniofacial development. How does one gene fulfill all these roles? Fgf8 codes for eight splice variants that produce distinct protein isoforms that vary in their N-termini and receptor binding affinity. As the authors suggest, the answer may lie in the concerted action of different isoforms depending on the cellular context. How the expression of the different splice variants is controlled during development remains an exciting area of study.

The article by K. Tremblay explores the cell movements and signaling events that specify the liver. Three major signaling pathways, FGF, BMP, and WNT are the main players in liver budding events in mice. However, as stressed by the author, the challenge to liver research is to link morphological changes with changes in gene expression prior to and at the onset of liver induction as they occur in the embryo. Here, cell fate studies of liver precursors take center stage since they can be used to link patterns of gene expression to precursors in the endoderm or to indicate target tissues for high throughput studies that in turn will create novel avenues of research.

It is increasingly being recognized that epigenetic abnormalities are the root cause of disease pathogenesis. For example, recent studies suggest that cancer is caused by pathological epigenetic changes (Berdasco and Esteller, 2010).

As evidenced in this series, the early mouse embryo is a premier setting for studying the mechanisms that orchestrate and maintain the epigenetic changes that establish cell fate. As such, the study of early mouse embryogenesis has pragmatic reverberations that resonate far beyond the fundamental goal of deciphering how the mouse embryo is shaped.